1. Field of the Invention
Hemostatic materials made from chitosan are provided, more particularly, chitosan shards having reduced pyrogenicity.
2. Description of the Related Art
Surgical procedures and traumatic injuries are often characterized by massive blood loss. Conventional approaches such as manual pressure, cauterization, or sutures may be time consuming and are not always effective in controlling bleeding.
Over the years, a number of topical hemostatic agents have been developed to control bleeding during surgical procedures and to control bleeding resulting from traumatic injury. Some agents such as collagen-based powders, sponges, or cloths are of a particulate nature. Particulate hemostatic agents provide a lattice for natural thrombus formation, but are unable to enhance this process in coagulopathic patients. Microfibrillar collagen, a particulate hemostatic agent, comes in powder form and stimulates the patient's intrinsic hemostatic cascade. However, this product has been reported to embolize and induce a localized inflammatory response if used during cardiopulmonary bypass. Further, particulates such as powders and even gels are difficult to control, and are easily carried away from an active bleeding site.
Pharmacologically-active agents such as thrombin can be used in combination with a particulate carrier, for example, as in a gelfoam sponge or powder soaked in thrombin. Thrombin has been used to control bleeding on diffusely bleeding surfaces, but the lack of a framework onto which the clot can adhere has limited its use. The autologous and allogenic fibrin glues can cause clot formation, but do not adhere well to wet tissue and have little impact on actively bleeding wounds.
Chitosan, the N-deacetylated derivation of chitin, has demonstrated hemostatic effectiveness as well as biocompatibility, biodegradability, and anti-bacterial activity. Chitosan has been shown to secure mucoadhesion and hemostasis despite defibrination and anticoagulation. FDA approved topical chitosan hemostats include Celox™ (a granular powder) and HemCon (a lyophilized chitosan film). Also FDA approved, for external use, is a microfibrillar high molecular weight chitosan in the form of sponge, puff or non-woven fabric.
Although chitosan has been shown to be an effective hemostat, the traditional, inexpensive methods for manufacturing commodity-grade chitosan yields a product that is laden with pyrogens, particularly endotoxins, which limit its applicability in the biological and medical arenas, as minute amounts of endotoxins may induce septic responses when contacted with mammalian tissue.
Experimental and biocompatibility artifacts are generated by unappreciated endotoxins in commercially available, “medical grade” chitosan. For example, an “ultra-pure” chitosan (PROTASAN™ S-213 fop, NovaMatrix™, a business unit of FMC BioPolymer, Sandvika, Norway) was advertised as having an endotoxin burden <100 EU/gm, a level that prohibits implantation but allows topical applications. However, an independent analysis of Protasan S-213 found endotoxin levels in the hemostat to be 247 EU/gm, over two times higher than the manufacturer's guaranteed level. Additionally, a medical-grade chitosan marketed as POLYPROLATE™ derived from Dungeness crab shells (Scion Cardio-Vascular, Inc., Miami, Fla.) has an EU level at 28 EU/gm. The FDA requires an EU level below 20 EU/gm for implantable medical devices which includes chitosan hemostats. The lack of an FDA-approved, implantable depyrogenated chitosan has halted advancements and development of promising techniques utilizing internal or implantable chitosan materials.